1. Field of the Invention
The present invention relates generally to the fields of molecular biology and genetics. More particularly, the invention provides compositions, methods and uses for identifying persons at an increased risk of infection by, transmission of, or accelerated progression of a disease caused by an HIV-1 virus. Diagnostic, prognostic and combined therapeutic kits are also provided.
2. Description of Related Art
Infection with HIV and the resulting diseases, including full-blown AIDS, remain a significant worldwide health problem. Methods are urgently needed to further understand the infection and transmission process and factors that pre-dispose certain individuals to increased risks.
Results from studies on the viral and host genetic and immunological factors that influence in HIV pathogenesis have been reported (Cairns and D'Souza, 1998; Berger, 1997; Fauci, 1996; Cohen et al., 1997; Buchacz et al., 1998; Rosenberg and Walker, 1998; Ferbas, 1998; Shearer and Clerici, 1998; Graziosi et al., 1998). Among the host factors that influence HIV-1 pathogenesis are non-MHC genetic determinants (chemokine system gene variants), MHC genetic determinants (HLA and linked genes), and chemokine related inhibition of HIV-1.
Several chemokine receptors have been identified as co-receptors with CD4 for HIV (Deng et al., 1996; Doranz et al., 1996; Moore et al., 1997; Cairns and D'Souza, 1998; Berger, 1997; Cohen et al., 1997; Feng et al., 1996; Choe et al., 1996; Deng et al., 1997; Zhang et al., 1998; Garzino-Demo et al., 1998; Berger et al., 1998; Unutmaz et al., 1998; Bjorndal et al., 1997; D'Souza and Harden, 1996; Fauci, 1996). These include CCR5, used preferentially by macrophage-tropic strains (M-tropic; non-synctium inducing (NSI); R5), and CXCR4, utilized by T-cell-tropic strains (T-tropic; synctium inducing (SI); X4). In addition, several R5 strains can use CCR2B or other co-receptors, although the role of this expanded receptor repertoire in vivo is not clear.
Analyses of different receptor alleles in HIV-1 patients have led to conflicting information regarding their importance to infectivity and disease progression (Dean et al., 1996; Michael et al., 1997a; 1997b; Zimmerman et al., 1997; de Roda Husman et al., 1997; Rizzardi et al., 1998; Meyer et al., 1997; Katzenstein et al., 1997; Eugen-Olsen et al., 1997; 1998; Hendel et al., 1998; Huang et al., 1996; Smith et al., 1997; Kostrikis et al., 1998; Anzala et al., 1998; van Rij et al., 1998; Rizzardi et al., 1998; Hendel et al., 1998).
In the U.S., the genetic determinants of HIV-1 in adults have been examined primarily in three different cohorts, each differing in risk factors for HIV-1 (Dean et al., 1996; Huang et al., 1996; Michael et al., 1997a; 1997b; Smith et al., 1997; Zimmerman et al., 1997; Winkler et al., 1998; Kostrikis et al., 1998; Martin et al., 1998; McDermott et al., 1998). They include multi-center cohort studies biased towards homosexual, Caucasian men (Multicenter AIDS cohort study (MACS); San Francisco City Cohort); hemophiliacs (Multicenter Hemophilia Cohort Study); and the single African-American cohort that is biased heavily towards an intravenous drug using population (AIDS link to Intravenous Experience (ALIVE)).
Despite such multi-center studies, it is unclear whether the results of the reported associations can be generalized to other ethnic/population groups. More recent publications have proposed associations of certain receptor promoter polymorphisms with an accelerated disease course in Caucasians (Martin et al., 1998; McDermott et al., 1998). However, as with the studies described above, the promoter studies attempt to correlate the association of promoter polymorphisms with an accelerated disease course, without consideration of the complete genotypic information present in the study group.
Therefore, it is evident that the art still needs improved methods of correlating the risk of infection by, transmission of, or accelerated progression of diseases caused by HIV-1. In particular, correlative methods that take into consideration all of the relevant genotypic (haplotype pairs) information, thus providing a stronger correlation, would represent a significant advance in this field.